The Effect of Adding Procalcitonin to the Systemic Inflammatory Response Syndrome (Sirs) and Quick Sepsis-Related Organ Failure Assessment (qSOFA) Scoring System in Predicting Sepsis Mortality

Objective: The primary objective of this study was to determine if the addition of procalcitonin to the existing systemic inflammatory response syndrome (SIRS) and quick Sepsis-related Organ Failure Assessment (qSOFA) scoring systems could improve the predictability of in-hospital sepsis-related mortality. Secondarily, we sought to determine if the addition of procalcitonin could predict the likelihood of ICU admission and discharge home. Design: This is a retrospective, single-center, observational study that looked at data from January 1, 2017 to January 1, 2019. Patients were stratified into four groups: SIRS-positive + procalcitonin >2 ng/mL (pSIRS+), SIRS-positive + procalcitonin ≤2 ng/mL (pSIRS-), qSOFA-positive + procalcitonin >2 ng/mL (pqSOFA+), and qSOFA-positive + procalcitonin ≤2 ng/mL (pqSOFA-). Setting: The study was conducted at a community hospital in Las Vegas, Nevada. Patients: Patients were included in the study if they were >18 years of age and had hospital admission diagnosis of sepsis with at least one value of procalcitonin level. Interventions: After patients which met the inclusion criteria, patients were divided into subgroups of SIRS, SIRS + procalcitonin > 2 ng/mL, qSOFA, qSOFA + procalcitonin >2 ng/mL. Primary outcomes were in-hospital mortality and secondary outcomes were ICU admission, length of stay, and discharge to home. Results: 933 patients were included in the study with an overall mortality rate of 21.22%, an overall ICU admission rate of 56.15%, and an overall discharge home rate of 29.58%. In those identified with a sepsis-related diagnosis code, pSIRS+ predicted an in-hospital mortality rate of 31.89% compared to pSIRS- 16.15% (P < 0.0001). In regards to qSOFA, the addition of procalcitonin added no statistically significant difference in predicting in-hospital mortality. pSIRS+ patients were found to have an ICU admission rate of 76.16% and a discharge home rate of 19.20% compared to pSIRS- who had 47.40% and 34.90%, respectively (P < 0.0001). Like in our primary outcome, our data for qSOFA was not statistically significant. Conclusions: Procalcitonin added utility to the SIRS scoring system in predicting sepsis-related in-hospital mortality, ICU admission, and discharge home. Procalcitonin did not add statistically significant benefit to the qSOFA scoring system in predicting sepsis-related in-hospital mortality, ICU admission, and discharge home.


Introduction
Sepsis remains a leading cause of mortality, with a mortality rate of over 210,000 people per year just in the United States alone [1]. There has been a 52.8% reduction in sepsis-related mortality from 1990 to 2017 largely due to the efforts of the Surviving Sepsis Campaign to identify and treat sepsis early [2]. Both systemic inflammatory response syndrome (SIRS) criteria and quick Sepsis-related Organ Failure Assessment (qSOFA) have been studied for the early identification of sepsis patients [3]. SIRS criteria were first utilized in 1992 with the initial Surviving Sepsis Guidelines, however, it has been criticized as lacking specificity [3]. In 2016, qSOFA was introduced as a replacement for the SIRS scoring system, however, it lacked sensitivity [3,4]. Procalcitonin has definite utility as a marker of severe systemic inflammation, infection, and sepsis [5]. Discontinuation of antibiotics for lower respiratory tract infections based on procalcitonin levels have shown to reduce the use of antibiotics without worsening adverse outcomes [6,7]. Guidelines do recommend the use of procalcitonin measurements to decrease antibiotic use [8]. Through our literature review, procalcitonin has been utilized as an adjunct to help increase the accuracy of our sepsisrelated screening tools [9]. In addition, procalcitonin has also been found to predict mortality in severe sepsis patients [10]. The relationship between procalcitonin and sepsis-related scoring systems has yet to be thoroughly studied in terms of in-hospital mortality, ICU admission rates, and discharge location. Our goal was to explore this relationship in an attempt to gain an objective marker to predict those who are at high risk for prolonged hospitalizations and subsequent complications.

Objectives
The primary objective of this study was to determine if the addition of procalcitonin to the existing SIRS and qSOFA scoring systems could improve the predictability of in-hospital sepsis-related mortality. Secondarily, we sought to determine if the addition of procalcitonin could predict the likelihood of ICU admission and discharge home.

Study Design and Location
This was a retrospective, single-center, observational study that took place from January 1, 2017, to January 1, 2019. The study was conducted at a community hospital in Las Vegas, Nevada.

Inclusion and Exclusion Criteria
All patients ≥18 years of age that presented to the hospital during the specified dates above were considered for inclusion in the study as long as they has at least one of the following documented in the chart: respiratory rate, heart rate, temperature, blood pressure, WBC, procalcitonin, and at least one sepsis-related diagnosis. Patients who were missing any of the above-aforementioned values were excluded from the study.

Statistical analysis
Mortality was analyzed by chi-square testing using Statistical Analysis System (SAS) when comparing pSIRS+, pSIRS-, pqSOFA+, and pqSOFA-. ICU admission and discharge home were analyzed with Fisher's exact testing using SAS between the four groups.

Results
A total of 933 total patients were included from January 1, 2017 to January 1, 2019 after inclusion and exclusion criteria were applied. We observed an overall mortality rate of 21 When comparing patient characteristics between those alive at discharge and those who died during their hospitalization, there was a predominance of older males who had an ICU stay during their hospitalization ( Table 1).  Comorbidities like end-stage renal disease, diabetes mellitus, and hypertension were similar between groups; however, pneumonia was 12% higher in those that died during their hospitalization. 74% of those that died during their hospitalization had pneumonia compared to 62% of those that were alive at discharge.

Mortality
The overall mortality rate of our study was 21.22% (198/933) with 56.16% (524/933) of our participants having stayed in the ICU during their hospitalization. According to National Center for health statistics, the septicemia hospital death rate increased by 17% from 2000 to 2010 [11]. The number of inpatients who died in the hospital with a first-listed diagnosis of septicemia also increased-it tripled from 45,000 in 2000 to 132,000 in 2010 [11]. Since our primary goal was to determine if the addition of procalcitonin to the existing SIRS and qSOFA scoring systems could improve the predictability of in-hospital sepsis-related mortality, our inclusion criteria selected for septic patients. This effect was intentional in order to test our hypothesis. Of note, this data was collected pre-COVID-19 pandemic.

Primary and secondary outcomes
The goal of the initial SIRS scoring system in 1991 was to create a highly sensitive set of parameters in order to establish a time-sensitive approach to the diagnosis of sepsis and initiation of early intervention to reduce morbidity and mortality. However, by doing so, the unavoidable corollary was a lack of specificity, which prompted the development of the qSOFA scoring system in 2016 [12,13]. Although the new scoring system was more specific for sepsis and was a better predictor of in-hospital mortality and organ dysfunction in non-ICU and ER patients, it too had its pitfalls-a low sensitivity [14][15][16][17][18]. This prompted the search for a biomarker that could potentially assist in our quest to find a screening tool that was both sensitive and specific. Procalcitonin is one such biomarker that has been shown to rise rapidly in lieu of bacterial infection making it an ideal biomarker for improved diagnostic and prognostic value [19][20][21][22][23][24]. With this framework and background, our data can be better interpreted.
In regards to the SIRS scoring system, the addition of procalcitonin >2 ng/mL proved to be a statistically significant tool in determining in-hospital mortality, ICU admission, and discharge home when compared to procalcitonin ≤2 ng/mL. Our data is consistent with the procalcitonin literature as stated earlier and improved SIRS prognostic value, which was inherently poor. Our results demonstrate the utility of procalcitonin in aiding clinicians in determining who is most at-risk for death during their hospitalization. This is a critical tool in guiding clinicians' decision-making as it can trigger earlier discussions about the goals of care. Palliative consultations before day 5 have been shown to reduce the length of stay and the financial burden on the healthcare system [25][26][27][28][29]. In addition, this can also initiate more aggressive management from admission and identify those most at risk for ICU admission.
The addition of procalcitonin to qSOFA did not show a statistically significant difference; however, the data still tended to correlate with our SIRS data. This is not entirely surprising as the utility of qSOFA is mainly a prognostic tool for morbidity and mortality. Therefore, the addition of another prognostic tool like procalcitonin would not presumably add a significant contribution. With that being said, we are not entirely certain this was the sole case. It could be possible that our information-gathering process itself (we utilized different diagnoses for altered mental status, refer to Table 4 in the appendices) may have underestimated the number of patients meeting the two-out-of-three criteria for a positive qSOFA score leading to an insignificant p-value.
Our study has multiple limitations. Firstly, patients with qSOFA scores might have been under or overestimated as only discharge diagnoses similar to altered mental status were used to classify patients into qSOFA. Secondly, only patients who had procalcitonin levels drawn were included in the study and so ICU patients who had no procalcitonin level were not included in the study. Thirdly; this being an observational study, it might have selection bias as only patients admitted with sepsis discharge diagnosis were included in the study. Even after multiple limitations, our study gives a unique insight into improving the SIRS score for predicting sepsis mortality.
Our results demonstrate that the utility of procalcitonin along with SIRS necessitates further prospective studies to validate its use as a predictor of clinical outcomes in sepsis.

Conclusions
We conclude that procalcitonin added utility to the SIRS scoring system in predicting sepsis-related inhospital mortality, ICU admission, and discharge home. This can assist clinicians in identifying patients with higher mortality and help triage resources appropriately. Procalcitonin did not add statistically significant benefit to the qSOFA scoring system in predicting sepsis-related in-hospital mortality, ICU admission, and discharge home.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. HCA IRB issued approval 2019-541-MountainView Hospital. Protocol was initially submitted to IRB. IRB reviewed the study and approval was obtained. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.